ABSTRACT CORE B: Immunology Core Core Director: Roberto Calcedo, Ph.D. We are entering a new era for treating inherited genetic disorders where gene therapy holds great promise for their treatment. After several decades of research and development in viral vectors, we finally have the technology to efficiently transfer genes into cells. Unfortunately, several studies have shown that immune responses to the viral vector and transgene heavily influence in vivo gene therapy performance. The Immunology Core focuses its efforts on studying the natural existing T and B cell immunity to viral vectors used in gene therapy, Adenovirus (AdV) and Adeno-associated virus (AAV), in human and nonhuman primates (NHPs). We have also centered our studies on vector and transgene-specific T and B cell responses after systemic and local administration of various rAAV and rAdV serotypes carrying different transgenes in NHPs and in subjects from several ongoing clinical trials. This will help us to determine if rAAV and rAdV administration can re-activate existing or induce new T cell responses to the vector or the transgene and if these have any effect on the outcome of the gene transfer and the health of the patient. We are also interested in T cell responses to self-antigens especially in those subjects with genetic diseases where a significant portion of the gene is missing. Introduction of the correct copy of the gene in these subjects could induce an immune response to the transgene and compromise the treatment. We are evaluating these responses in CF subjects and found low to high levels of self-reactive CFTR-specific T cells directed to the mutated region of the CFTR. In all these studies, we isolated lymphocytes from blood, liver, intestine, primary and secondary lymphoid organs and characterized the T cell response by ex vivo IFN? ELISPOT, lymphoproliferation assay, in vivo CTL assay, and polychromatic flow cytometric analysis of antigen specific T cells. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page